The following description of the background of the invention is provided to aid in understanding the invention, but is not admitted to be, or to describe, prior art to the invention. All publications are incorporated by reference in their entirety.
Compounds containing phosphonic acids and their salts are highly charged at physiological pH and therefore frequently exhibit poor oral bioavailability, poor cell penetration and limited tissue distribution (e.g., CNS). In addition, these acids are also commonly associated with several other properties that hinder their use as drugs, including short plasma half-life due to rapid renal clearance, as well as toxicities (e.g., renal, gastrointestinal, etc.) (e.g., Bijsterbosch et al., Antimicrob. Agents Chemother. 42(5): 1146-50(1998)).
Phosphonic acid ester prodrugs can be used to improve the oral bioavailability, cell penetration and tissue distribution of drugs containing a phosphonic acid moiety. The most commonly used prodrug class is the acyloxyalky ester, which was first applied to phosphate and phosphonate compounds in 1983 by Farquhar et al., J. Pharm. Sci. 72: 324 (1983). This strategy has proven successful in the delivery of phosphates and phosphonates into cells and in the oral absorption of phosphates, phosphonate's and phosphinic acids. For example, the bis(pivoyloxymethyl) prodrug of the antiviral phosphonate, 9-(2-phosphonylmethoxyethyl)adenine (PMEA), has been studied clinically for the treatment of CMV infection and the bis(pivaloyloxymethyl) prodrug of the squalene synthetase inhibitor, BMS188494 has been evaluated as a treatment of hypercholesterolemia and associated cardiovascular diseases. The marketed antihypertensive, fosinopril, is a phosphinic acid angiotensin converting enzyme inhibitor that requires the use of an isobutryloxyethyl group for oral absorption. A close variant of the acyloxyalkyl ester strategy is the use of alkoxycarbonyloxyalkyl groups as prodrugs. These prodrugs are reported to enhance oral bioavailability.
Other examples of suitable phosphonate prodrugs include proester classes exemplified by Krise et al. (Adv. Drug Del. Rev. 19: 287 (1996)); and Biller and Magnin (U.S. Pat. No. 5,157,027).
Cyclic phosphonate esters have also been shown to decrease serum lipids and treat atherosclerosis (U.S. Pat. No. 5,962,440). Other examples of phosphonate esters are exemplified by Prisbe et al. (J. Med. Chem. 29: 671 (1986)); and Ozoe et al. (Bioorg. Med. Chem. 6: 73 (1998).